Mouse strains with mutations in major histocompatibility loci have proved extremely useful for genetic and immunologic investigations of MHC antigens. The first mutation (bm12) discovered in an I-A gene has already provided several new insights into structural and functional properties of Ia molecules, including direct genetic evidence that Ia antigens are identical with the cell surface molecules which regulate the immune response (the putative Ir gene products). The further studies using bm12 mice proposed in this application should allow precise correlations between structural changes in Ia molecules and resulting serologic and functional changes. The T-cell recognition and humoral responses to restricted Ia antigenic determinants will be studied using cloned T-cell lines, monoclonal and alloantisera, and antiidiotypic reagents. Immune functions, known to involve Ia, such as response to insulins of various species, haplotype-specific suppression and skin graft enhancement, will be investigated using bm12 mice. Using similar approaches, newly discovered Ia mutants (variants) will be serologically, chemically and functionally characterized, and each of these strains should elucidate new insights into the immunologic role of individual I region gene products.